Scientists at work. Courtesy 2019 Fotolia
Scientists at work. Courtesy 2019 Fotolia

The investigational anti-cancer agent GTB-1550, also known as OXS-1550 or DT2219 is a novel multi-target directed therapy for the treatment of chemotherapy-refractory B-cell malignancies, including Non-Hodgkins Lymphoma and Leukemia being developed by clinical stage biopharmaceutical company GT Biopharma.

The company has completed one dose escalation Phase I-II expansion clinical trial, and one fixed dose Phase I-II expansion clinical trial which collectively enrolled a combined 43 patients.

Simultaneously targeting cancer cells
GTB-1550 is a novel, multi-target bispecific cytotoxic therapeutic agent consisting of diphtheria toxin and bispecific single-chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. By simultaneously targeting cancer cells that express either CD19 or CD22 or both, GTB-1550 is capable of killing a broader variety of hematological malignancies than either a traditional a CD19 Antibody-drug Conjugate (ADC) or a CD19 Chimeric Antigen Receptor T-cells (CAR T) immunotherapy which are only able to target and attack CD19 expressing hematological malignancies.

Simultaneously targeting multiple cancer targets such as CD19 and CD22, using a single therapeutic agent, has the potential to makes this multi-target bispecific drug-conjugate therapy one of the first next generation of advanced cancer therapies.

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Greater than 50% of Evaluable Patients Receiving 60 mg/kg Dose had Positive Clinical Response

Trial design
In this trial, patients receive a single course of the investigational agent as a 4 hour infusion on days 1, 3, 5, and 8. Weekly follow-up will continued through day 29, at which time a disease reassessment was done. For patients in remission, follow-up will continued monthly until disease progression or start of a new treatment.

This phase I study used a Continual Reassessment Method (CRM) design, a type of adaptive dose-finding study, to establish a maximum tolerated dose (MTD) of GTB-1550. The researchers used this trial design because it tends to incur fewer toxic events, and more accurately estimate the maximum tolerated dose as compared to the standard Phase I dose escalation designs.

In this trial the researchers investigated up to 3 dose levels with an additional dose level (-1) if dose level 1 proves too toxic. The goal of the CRM was to identify the dose level which correspondences to a desired toxicity rate of 33% or less using grade 3 or 4 capillary leak syndrome and any grade 3 or greater toxicity attributed to GTB-1550 as the targeted toxicity. These goals were based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

Trial results

  • Two patients exhibited a Complete Remission (CR) with one patient currently disease-free at 50 months post treatment.
  • Five patients exhibited Stable Disease (SD), cancers that are neither increasing or decreasing in severity, with the longest response lasting 12 months post treatment.
  • Two patients with transformed lymphoma showed transient tumor shrinkage, however, therapy was discontinued due to dose-limiting toxicities after the 1st cycle.
  • Greater than 50% of evaluable patients, (patients where response to treatment can be measured because enough data has been collected), receiving 60 mg/kg dose had positive clinical response defined as stable disease, partial remission, or complete remission.
Veronika Bachanova, MD, PhD, Associate Professor of Medicine, Division of Hematology, Oncology and Transplantation, at the University of Minnesota.

“We are pleased the patient who experienced a complete remission following treatment with GTB-1550 is doing well, and we are excited about moving forward with a GTB-1550 Phase II clinical trial for the treatment of chemotherapy-refractive B-cell malignancies,” noted Veronika Bachanova, MD, Ph.D, Associate Professor of Medicine, Division of Hematology, Oncology and Transplantation at the University of Minnesota and the Principal Investigator for both clinical trials.

“GTB-1550 has shown positive results in its two Phase I-II clinical trials in advanced cancer patients who have failed all other therapies, and we are now planning to proceed with a Phase II clinical trial,” said Anthony Cataldo, the Chairman and Chief Executive Officer of GT Biopharma.

The initial Phase I-II expansion clinical trial (NCT00889408) demonstrated decreased tumor mass in one patient, and a complete response in a second patient that remains on-going at 50 months post treatment. After a single course of GTB-1550 (DT2219) at dose level 40 mg/kg/day x 4, a 77-year-old patient with chemotherapy-refractory CD19+/CD22- chronic lymphocytic leukemia (CLL) experienced a 40% reduction in cervical and axillary adenopathy with decrease of an abdominal tumor mass at day 28 after treatment, which was sustained for 2 months. [A][1]

The second clinical response occurred in a 53-year-old patient with relapsed CD19+/CD22+ diffuse large B cell lymphoma (dose level 60 mg/kg) who experienced a 75% reduction in size of lymphoma lesion after a single course complicated by a grade 3 capillary leak syndrome.

Eight weeks later after the U.S. Food and Drug Administration (FDA) approval, this patient received a second DT2219 course at a reduced dose of 40 mg/kg/dose for 4 days, which resulted in a complete resolution of a subcutaneous mass and pelvic lymphadenopathy.

This patient is alive and in complete remission with no neutralizing antibodies, currently at 50 months after therapy.

Phase I – II expansion trial
Results of the second GTB-1550 Phase I-II expansion trial (NCT02370160) targeting CD22 and CD19 for treatment of refractory B-cell malignancies, presented on-line in conjunction with the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago from May 31June 4, showed treatment was well tolerated at 60 mg/kg x 8 doses. The most common adverse events included capillary leak syndrome, elevated AST/ALT, low albumin, weight gain and leukopenia.[B] [2]

All adverse events were Grade 1-2 and resolved after 3-5 days allowing day 15 GTB-1550 administration. There were no neutropenic fever or immune mediated adverse events.

  • Four patients experienced dose limiting toxicity (DLT) at dose 80 μg/kg/day: Grade 4 capillary leak syndrome (n=1), Grade 3 liver function test (LFT) abnormalities (n=2) and Grade 4 thrombocytopenia >7 days duration (n=1).
  • Thirteen patients were evaluable for response, and 3 experienced objective clinical benefit.
  • One patient with primary refractory pre-B acute lymphoblastic leukemia achieved complete remission after 1st cycle.
  • Two patients with transformed lymphoma demonstrated transient tumor shrinkage, however, GTB-1550 therapy was discontinued due to DLT and increased neutralizing antibody titer after 1st cycle (pre C1 28%, pre C2 108%).

Correlative studies demonstrated a low incidence of neutralizing antibody in Non-Hodgkin Lymphoma (NHL) patients recently exposed to rituximab (Rituxan®; Genentech/Roche).

The researchers have established the biologically active dose of GTB-1550 (DT2219) at 60 μg/kg/day ×8 doses. Further development of the investigational agent includes combination with rituximab (to reduce the formation of neutralizing antibody (NA) against diphteria toxin) and synergistic combinations against B-cell malignancies.

Clinical trials
[A] DT2219ARL for Relapsed or Refractory CD19 (+), CD 22 (+) B-Lineage Leukemia Or Lymphoma – NCT00889408
[B] HM2014-26 DT2219 for Relapsed or Refractory B-Lineage Leukemia or Lymphoma – NCT02370160

[1] Bachanova V, Frankel AE, Cao Q, Lewis D, Grzywacz B, Verneris MR, Ustun C, et al. Phase I study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies. Clin Cancer Res. 2015 Mar 15;21(6):1267-72. doi: 10.1158/1078-0432.CCR-14-2877. [Pubmed][Article]
[2] Bachanova V, Cao Q, Weisdorf DJ, Curtsinger JM, Cooley SA, Miller J, Vallera D. Bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies: Results of phase I-II trial. J Clin Oncol 37, 2019 (suppl; abstr e19066) [Abstract]